Cardiovascular disease (CVD) is a term for heart and blood vessel diseases, including—among others—ischemic heart disease (being the most common type of CVD in the industrialized countries; this disorder refers to problems with the circulation of the blood to the heart muscle), cerebrovascular disease (refers to a problem with the circulation of the blood in the blood vessels of the brain), and peripheral vascular disease (affecting the circulation primarily in the legs). Subjects with CVD may develop a number of complications (hereinafter referred to as CVD complications) including, but not limited to, myocardial infarction, stroke, angina pectoris, transient ischemic attacks, congestive heart failure, aortic aneurysm and death.
The Framingham Heart Study (Kamel W B et al. Am J Cardiol 1988; 62:1109-1112., Wilson P W F et al., Circulation 1988; 97:1837-1847, Grundy S. M. et al. Circulation 1988; 97:1876-1887) was a pioneering study in the development of the concept of risk factors, which is widely used and accepted today. Several independent risk factors have been recognized to be the direct cause of coronary disease and are frequent factors in the population, and their modification reduces the risk of coronary (i.e. cardiovascular) events (Grundy S. C. et al., Circulation 2000; 101:e3-e11). The main modifiable risk factors are smoking, high blood pressure, hypercholesterolemia (in particular high LDL-cholesterol) and diabetes mellitus (Circulation 2000; 101:e3-e11).
The adaptation of all actions according to the absolute risk (the probability that a person develops a coronary disease in a certain period of time) is important, because it allows to reach a suitable balance between efficacy, safety and therapy costs. The estimation of the absolute risk requires adding up the contribution of each risk factor and the result is “the determination of the global risk”. The Framingham Heart Study, as mentioned above, performed a quantitative estimation of the global risk based on the contribution of each risk factor that has served other Societies to develop other algorithms for other populations. The incidence and emergence of cardiovascular disease in Europe differs significantly from the USA, and the Framingham scale has been reported to overestimate cardiovascular risk in the European population (Moreno J et al., Rev Med Univ Navarra 2005; 49:109-115).
For this reason, two scales have been developed to estimate cardiovascular risk in Europe: the PROCAM scale that estimates the risk of cardiovascular complications (Assman G et al., Circulation 2002; 105:310-315) and the SCORE Project (Conroy R. M. et al., Eur Heart J 2003; 24:987-1003), which estimates the risk of cardiovascular death.
However, in spite of all efforts made to estimate risk and despite the recommendation to estimate the global cardiovascular risk in all patients, a considerable number of cardiovascular events occur in asymptomatic patients with an intermediate risk according to the risk assessment tools (Circulation 2001; 104:1863-1867).
Patients with an intermediate risk would significantly benefit from the use of more tests that allowed a more precise stratification of their risk (Circulation 2001; 104:1863-1867, Am J Cardiol 2006; 97 [Suppl]:28A-32A).
Several studies have identified genetic markers which associate with the risk of suffering a CVD.
In particular, three studies which are analyzing if the incorporation of genetic information in the classic functions of risk improves their predictive and discriminatory capabilities have been published. The first one published by Morrison et al., (Am J Epidemiol. 2007 Jul. 1; 166(1):28-35) with a follow-up of more than 15.000 participants of the study ARIC, constructed in this cohort a scale of genetic risk including 11 polymorphisms. However, this function does not improve the capacity of discrimination of the classic risk factors (the area under the curve ROC was increasing only slightly from 0.764 to 0.766).
The second one, published by Kathiresan et al. (N Engl J Med. 2008 Mar. 20; 358(12):1240-9) also used a function of genetic risk including 9 polymorphisms related to lipid metabolism, also based on the number of alleles of risk in each subject. This function of genetic risk was independently related to the appearance of cardiovascular events in the cohort of Malmo. Though this punctuation was not improving the capacity of discrimination of the classic risk factors (area under the curve ROC, 0,8 with and without the genetic information), the reclassification was improved.
The third and most recent paper was a study performed in a cohort of American nurses. The incorporation of the genetic variability in the chromosome 9p21.3 does not improve the capacity of discrimination (area under the curve ROC from 0,807 to 0,809) nor the reclassification of individuals with regard to that obtained with the classical risk factors (Ann Intern Med. 2009 Jan. 20; 150(2):65-72).
Therefore, despite several attempts made to improve the prediction power of the CVRF this goal has not yet been accomplished.
Accordingly, there is a need for novel markers, including new genetic markers and combinations thereof that could successfully and advantageously predict who is at higher risk of developing classical cardiovascular risk factors in a way that preventive measures could be implemented to keep the cardiovascular risk at the lower possible level.